Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of microRNA-224

Hepatology. 2014 Feb;59(2):505-17. doi: 10.1002/hep.26659. Epub 2013 Dec 13.

Abstract

In hepatocellular carcinoma (HCC), dysregulated expression of microRNA-224 (miR-224) and impaired autophagy have been reported separately. However, the relationship between them has not been explored. In this study we determined that autophagy is down-regulated and inversely correlated with miR-224 expression in hepatitis B virus (HBV)-associated HCC patient specimens. These results were confirmed in liver tumors of HBV X gene transgenic mice. Furthermore, miR-224 was preferentially recruited and degraded during autophagic progression demonstrated by real-time polymerase chain reaction and miRNA in situ hybridization electron microscopy after extraction of autophagosomes. Our in vitro study demonstrated that miR-224 played an oncogenic role in hepatoma cell migration and tumor formation through silencing its target gene Smad4. In HCC patients, the expression of low-Atg5, high-miR-224, and low-Smad4 showed significant correlation with HBV infection and a poor overall survival rate. Autophagy-mediated miR-224 degradation and liver tumor suppression were further confirmed by the autophagy inducer amiodarone and miR-224 antagonist using an orthotopic SD rat model.

Conclusion: A noncanonical pathway links autophagy, miR-224, Smad4, and HBV-associated HCC. These findings open a new avenue for the treatment of HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amiodarone / pharmacology
  • Animals
  • Autophagy / drug effects
  • Autophagy / physiology*
  • Carcinogenesis / metabolism*
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / virology
  • Disease Models, Animal
  • Down-Regulation
  • Hepatitis B / complications
  • Hepatitis B virus / physiology*
  • Humans
  • In Vitro Techniques
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / virology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Microscopy, Electron
  • Rats
  • Rats, Sprague-Dawley
  • Smad4 Protein / metabolism

Substances

  • MIRN224 microRNA, human
  • MIRN224 microRNA, mouse
  • MIRN224 microRNA, rat
  • MicroRNAs
  • Smad4 Protein
  • Amiodarone